Progressive familial intrahepatic cholestasis: From childhood to adulthood

Table 1 Genes associated with progressive familial intrahepatic cholestasis and related cholestatic disorders

Gene (HGNC)	Locus	Mechanism	Protein	PFIC type/phenotype	OMIM	Inheritance
ABCB11	2q31.1	Canalicular bile salt transport defects	Bile salt export pump	Cholestasis, benign recurrent intrahepatic 2	605479	AR
				Cholestasis, progressive familial intrahepatic 2	601847	AR
ABCB4	7q21.12	Canalicular phospholipid salt transport defects	Multidrug resistance protein 3	Cholestasis, intrahepatic, of pregnancy 3	614972	AD, AR
				Cholestasis, progressive familial intrahepatic 3	602347	AR
				Gallbladder disease 1	600803	AD, AR
ATP8B1	18q21.31	Membrane lipid homeostasis/canalicular stability	Familial intrahepatic cholestasis protein 1	Cholestasis, benign recurrent intrahepatic	243300	AR
				Cholestasis, intrahepatic, of pregnancy 1	147480	AD
				Cholestasis, progressive familial intrahepatic 1	211600	AR
TJP2	9q21.11	Tight junction/epithelial barrier defects	Tight junction protein 2	Cholestasis, progressive familial intrahepatic 4	615878	AR
				Hypercholanemia, familial 1	607748	AR
USP53	4q26	Tight junction/epithelial barrier defects	Ubiquitin-specific peptidase 53	Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss	619658	AR
NR1H4	12q23.1	Transcriptional regulation of bile acid homeostasis	Nuclear receptor subfamily 1 group H member 4	Cholestasis, progressive familial intrahepatic, 5	617049	AR
MYO5B	18q21.1	Intracellular trafficking and epithelial defects	Myosin Vb	Cholestasis, progressive familial intrahepatic, 10	619868	AR
				Diarrhea 2, with microvillus atrophy, with or without cholestasis	251850	AR
VPS33B	15q26.1	Intracellular trafficking and epithelial defects	Vacuolar protein sorting-associated protein 33B	Arthrogryposis, renal dysfunction, and cholestasis 1	208085	AR
				Cholestasis, progressive familial intrahepatic, 12	620010	AR
				Keratoderma-ichthyosis-deafness syndrome, autosomal recessive	620009	AR
ZFYVE19	15q15.1	Ciliopathy/cholangiocyte architecture defects	Zinc finger FYVE domain-containing protein 19	Cholestasis, progressive familial intrahepatic, 9	619849	AR
SLC51A	3q29	Enterohepatic bile acid transport defects	Organic solute transporter alpha	Cholestasis, progressive familial intrahepatic, 6	619484	AR
KIF12	9q32	Ciliopathy/cholangiocyte polarity defects	Kinesin family member 12	Cholestasis, progressive familial intrahepatic, 8	619662	AR
SEMA7A	15q24.1	Signaling/inflammatory modulation	Semaphorin-7A	Cholestasis, progressive familial intrahepatic, 11	619874	AR
PSKH1	16q22.1	Ciliopathy/epithelial polarity defects	Protein serine kinase H1	Cholestasis, progressive familial intrahepatic, 13	620962	AR

HGNC: HUGO Gene Nomenclature Committee; OMIM: Online Mendelian Inheritance in Man; PFIC: Progressive familial intrahepatic cholestasis; AD: Autosomal dominant; AR: Autosomal recessive.

Table 2 Mechanism-based clinical classification of progressive familial intrahepatic cholestasis integrating variant type, phenotype, and therapeutic implications

	Residual function present	Severe loss-of-function variants
Typical variant type	Missense variants; partial loss of function; reduced but preserved protein activity	Nonsense variants; frameshift variants; canonical splice-site variants; biallelic null variants
Mechanistic contexts	Canalicular transport defects: Selected ABCB11, ABCB4 variants. Membrane lipid homeostasis/canalicular stability: Selected ATP8B1 variants. Tight junction/epithelial barrier dysfunction: Selected TJP2, USP53 variants. Intracellular trafficking/polarity defects: Selected MYO5B variants	Canalicular transport defects: Truncating ABCB11, severe ABCB4. Membrane lipid homeostasis/canalicular stability: Severe ATP8B1. Tight junction/epithelial barrier dysfunction: Severe TJP2. Nuclear receptor/transcriptional regulation: NR1H4. Intracellular trafficking/polarity defects: Severe MYO5B, VPS33B
Genotype-phenotype correlation	Missense variants are often associated with residual protein activity. Genotype-phenotype correlation is evident in selected genes (e.g., ABCB11, ABCB4). Clinical severity varies widely depending on residual function. Milder or later-onset phenotypes may be observed	Truncating or null variants are associated with absent protein function. Strong genotype-phenotype correlation with severe clinical presentation. Early-onset disease and rapid progression are common. Higher risk of complications (e.g., liver failure, malignancy in selected subtypes)
Clinical implications	Variable severity. Later onset or slower progression may occur. Residual transporter activity may still permit bile flow	Early-onset, often neonatal or infantile. Rapid progression. Higher risk of advanced liver disease and complications
Therapeutic implications	IBAT inhibitors: More likely to be beneficial. UDCA: Especially relevant in ABCB4-related disease. Rifampicin/symptomatic therapy: May be useful for pruritus. PEBD/internal diversion: Can be considered in refractory cases with preserved native liver function	IBAT inhibitors: Limited or less predictable benefit. PEBD/internal diversion: Earlier consideration in progressive disease. Liver transplantation: Often required in severe or rapidly progressive cases. Multidisciplinary management: Especially important when extrahepatic involvement is present
Key determinant: Residual protein function is the primary driver of disease severity and therapeutic response across all PFIC mechanisms

PFIC: Progressive familial intrahepatic cholestasis; IBAT: Ileal bile acid transporter inhibitors; UDCA: Ursodeoxycholic acid; PEBD: Partial external biliary diversion.